This invention relates generally to synthetic polymer compositions that form interpenetrating polymer networks when administered to tissues. Such compositions are particularly well suited for use in a variety of medical applications when the physical strength of the administered material is important. For example, the compositions of the present invention that are designed to be used to attach tissues together are strong enough to provide an effective substitute for other surgical means of attachment, such as sutures and medical staples.
The use of polymer compositions in tissue engineering is now widely recognized, particularly those consisting of synthetic polymers. In contrast to many naturally derived compositions, synthetic polymer compositions can be formulated to exhibit predetermined physical characteristics such as gel strength, as well as biological characteristics such as degradability.
In a variety of tissue engineering applications, it is desirable to use compositions that can be administered as liquids, but subsequently form hydrogels at the site of administration. Such in situ hydrogel forming compositions are more convenient to use since they can be administered as liquids from a variety of different devices, and are more adaptable for administration to any site, since they are not preformed. Many different mechanisms have been described that can be used to promote hydrogel formation in situ. For example, photoactivatable mixtures of water-soluble co-polyester prepolymers and polyethylene glycol have been described to create hydrogel barriers, as well as drug release matrices. In another approach, block copolymers of Pluronic and Poloxamer have been designed that are soluble in cold water, but form insoluble hydrogels that adhere to tissues at body temperature (Leach, et al., Am. J. Obstet. Gynecol. 162:1317-1319 (1990)). Polymerizable cyanoacrylates have also been described for use as tissue adhesives (Ellis, et al., J. Otolaryngol. 19:68-72 (1990)). In yet another approach, two-part synthetic polymer compositions have been described that, when mixed together, form covalent bonds with one another, as well as with exposed tissue surfaces (PCT WO 97/22371) In a similar approach involving a two-part composition, a mixture of protein and a bifunctional crosslinking agent has been described for use as a tissue adhesive (U.S. Pat. No. 5,583,114.)
In other tissue engineering applications, it is not necessary or desired for the compositions to be in liquid form when administered. In fact, it may be advantageous in some circumstances to apply compositions that are gelatinous, paste-like, or even preformed solid implants, since these forms tend to stay in place after administration more readily than liquid formulations.
For many tissue engineering applications, it is important that the compositions be capable of forming a matrix after administration that is strong enough to withstand the biological and physical forces to which it will be subjected for a long enough period of time to fulfill its intended purpose. Strength is particularly important when the compositions are used as a partial or total replacement for sutures. In addition, for applications in which adherence to tissues is important, it is necessary for the formulations to have adequate adhesive strength. Cyanoacrylate is a highly effective adhesive that forms a strong matrix, but is too toxic to be used internally and is thus not approved for such uses. Accordingly, it is an object of the present invention to provide compositions that form high strength medical sealants that are not toxic.
The present invention relates to multifunctional polymer-containing compositions that are specifically designed to exhibit superior strength for one embodiment. The compositions comprise a first multifunctional synthetic polymer having m functional groups, X; a multifunctional crosslinking agent having n functional groups, Y; and a tensile strength enhancer, such that when all three components are mixed together, X and Y react to form a covalently bonded three-dimensional interpenetrating polymer network. In addition, the tensile strength enhancer may become covalently bonded in the network, or it may become physically entrapped therein.
In a preferred embodiment of the present invention, the multifunctional crosslinking agent is a second multifunctional synthetic polymer.
An aspect of the present invention is inclusion of the tensile strength enhancer, which can be comprised of a variety of compounds capable of forming a structure with the appropriate characteristics as described elsewhere herein. Such compounds include, inter alia, Vicryl, glass wool, plastics, resins, and fibers.
The functional groups, X and Y can be any pair of reactive moieties that form a covalent bond, Z, under the appropriate conditions, such as sulfhydryl, succinimidyl, acrilate and amino, which form, in no particular order, ether, ester or disulfide.
In order to enhance or discourage biodegradation of the interpenetrating polymer network, the synthetic polymer core may additional comprise a chain extender. For example, alpha-hydroxy acid, poly(lactone), poly(orthocarbonate) and poly(phosphoester) moieties may serve to enhance biodegradability. In addition, the chain extender may be an enzyme substrate.
In another aspect of the present invention, the composition further comprises optional components, such as proteins, antibiotics, growth factors and hemostatic agents.
In a preferred embodiment of the invention, the optional component is present in the form of a rigid nanofiber, such as that formed by methylated collagen.
In yet another aspect of the invention, X and Y are each 4 or greater to provide for more efficient crosslinking.
In one embodiment, the composition of the present invention comprises a pair of reactive polyalkylene oxides, a rigid nanofiber, such as methylated collagen, and a tensile strength enhancer.
Other aspects of the present invention are described elsewhere herein.